- Email: [email protected]
Circulating miR-128 as a potential diagnostic biomarker for glioma
Clinical Neurology and Neurosurgery 160 (2017) 88–91
Contents lists available at ScienceDirect
Clinical Neurology and Neurosurgery journal homepage: www.elsevier.com/locate/clineuro
Circulating miR-128 as a potential diagnostic biomarker for glioma Ruo-Fei Liang, Mao Li, Yuan Yang, Xiang Wang, Qing Mao, Yan-Hui Liu
⁎
MARK
Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, China
A R T I C L E I N F O
A B S T R A C T
Keywords: Glioma Circulating miR-128 Meta-analysis
Objective: miR-128 in circulation is a promising marker for early diagnosis of glioma. A meta-analysis was performed to evaluate the diagnostic accuracy and clinical value of circulating miR-128 in patients with glioma. Materials and methods: A comprehensive literature search for relevant published articles (last search updated on December 29, 2016) was conducted in the Chinese Biomedical Literature Database, PubMed, and Embase. The quality assessment of diagnostic accuracy studies (QUADAS) tool was used to score the quality of the eligible studies. Meta-Disc 1.4 software was used to test for heterogeneity and to perform the meta-analysis. Results: The three studies included in our study enrolled a total of 191 patients with glioma and 73 individuals without tumor. Using a fixed-effect model analysis, the summary assessments revealed that the pooled sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio were 0.89 (95% CI: 0.84–0.93), 0.90 (95% CI: 0.81–0.96), 8.07 (95% CI: 4.21–15.46), and 0.13 (95% CI: 0.09–0.19), respectively. The diagnostic odds ratio (DOR) of miR-128 was 65.00 (95% CI: 26.90–157.10), indicating that the overall accuracy of the miR128 test for detecting glioma was high. The value of I2 was 0.0%, indicating that there was no significant heterogeneity among studies. Conclusion: The present meta-analysis showed that circulating miR-128 might be a promising noninvasive biomarker for diagnosing glioma.
1. Introduction
involved in tumor development and progression through the dysfunctions of tumor suppressor genes and oncogenes [7]. As miRNAs are key molecules that determine cells’ fates, they could be used as potential biomarkers in tumor diagnosis. Pioneering studies have demonstrated the potential utility of tumor-specific miRNAs as diagnostic biomarkers for tumors in body fluids [8,9]. As a tumor-associated miRNA, miR-128 is strongly down-regulated in human glioma when compared with the corresponding samples of controls [10]. In recent years, additional studies have revealed that miR-128 is significantly down-regulated in the circulation of patients with glioma compared to that in individuals without tumor [11–13]. Therefore, we performed a meta-analysis to estimate the suitability of circulating miR-128 as a biomarker for the early diagnosis of glioma.
Gliomas are defined as tumors arising from glial cells, and they comprise more than 36% of all primary tumor of the central nervous system (CNS) and 80% of all malignant CNS tumors [1,2]. Glioblastoma (GBM) is the most common and malignant form of glioma, accounting for about 50% of all intracranial gliomas [3]. However, even with comprehensive treatment (surgical resection, radiation and chemotherapy), the prognosis is still poor for patients with newly diagnosed GBM; the 2-year survival rate is around 27% and the median survival is 14.6 months [4]. Therefore, investigation of potential minimally invasive biomarkers with high sensitivity and specificity for the early diagnosis of gliomas is urgently needed. The circulating biomarkers of glioma have become a major focus of research. MiRNAs are a class of endogenous small (approximately 20–24 nucleotides) noncoding RNAs that regulate specific target gene expression via a post-transcriptional manner [5]. They have been identified as key regulatory molecules involved in a variety of cellular functions and biological processes, such as metabolism, proliferation, apoptosis, and differentiation [6]. Not surprisingly, dysregulation of the miRNAs pathways affects many cellular functions and biological processes that are routinely altered in tumors. More specifically, they are
⁎
Corresponding author. E-mail address: [email protected] (Y.-H. Liu).
http://dx.doi.org/10.1016/j.clineuro.2017.06.020 Received 24 March 2017; Received in revised form 21 June 2017; Accepted 28 June 2017 Available online 05 July 2017 0303-8467/ © 2017 Elsevier B.V. All rights reserved.
2. Methods 2.1. Literature search A comprehensive literature search for relevant articles published (last search updated on December 29, 2016) in the Chinese Biomedical Literature Database (CBM), PubMed, and Embase was conducted. The key words used for the literature search included: hsa-miR-128; miRNA-
Clinical Neurology and Neurosurgery 160 (2017) 88–91
R.-F. Liang et al.
128; miR-128; microRNA-128; glioma; and brain tumor. No language restrictions were applied. All eligible articles were retrieved. All studies identified by our search strategy were assessed by 2 independent reviewers (Ruofei Liang and Mao Li). Any disagreements on controversial articles were resolved by discussion until a consensus was reached.
summarized in Table 1. Overall, the QUADAS scores of the included articles ranged from 12 to 12.5, which demonstrate that the quality of the articles is acceptable.
2.2. Literature selection
The sensitivity and specificity of miR-128 are shown on a forest plot (Fig. 1). The pooled sensitivity, specificity, PLR, and NLR were 0.89 (95% CI: 0.84–0.93), 0.90 (95% CI: 0.81–0.96), 8.07 (95% CI: 4.21–15.46), and 0.13 (95% CI: 0.09–0.19), respectively, which suggests that miR-128 could be a good blood test marker for glioma diagnosis. The diagnostic accuracy was assessed by the pooled DOR, which was 65.00 (95% CI: 26.90–157.10; Fig. 1), indicating that miR128 has a high diagnostic accuracy for diagnosing glioma. The value of I2 was 0.0%.
3.2. Data analysis
Eligible articles included in this study met the following criteria: (1) the diagnosis of glioma was made based on pathological confirmation; (2) they detected miR-128 in cerebrospinal fluid, plasma, or serum; (3) these studies investigated the relationship between miR-128 expression levels and glioma diagnosis; (4) they selected healthy people or patients with benign disease as the control group; and (5) the articles presented sufficient data to allow for construction of 2 × 2 tables. The exclusion criteria were as follows: (1) the patients were included in other studies; (2) these studies only detected tissue miR-128; (3) the articles were case reports, letters, or reviews; and (4) these articles could not provide enough data to allow construction of 2 × 2 tables.
4. Discussion In recent years, miRNAs have gained wide interests in tumor research for their pivotal role in gene regulation and tumor development. The potential role of miR-128 as a novel diagnostic or prognostic biomarker has been confirmed by accumulated evidence in multiple tumor types, such as prostate cancer, primary osteosarcoma, non-small cell lung cancer, colorectal cancer and acute leukemia [17–21]. An ideal diagnostic biomarker should be reliable, convenient and sensitive. The studies in our study detected circulating miR-128 expression using a qRT-PCR method. Tumor-derived miRNAs in serum or plasma are very accessible, and qRT-PCR is a commonly used analysis technology in clinical practice. Therefore, the purpose of this study was to evaluate the diagnostic role of circulating miR-128 in gliomas through metaanalysis. In the present meta-analysis, we included three studies with a total participant population of 264. We showed that circulating miR-128 can discriminate glioma from controls and had a pooled sensitivity and specificity of 0.89 (95% CI: 0.84–0.93) and 0.90 (95% CI: 0.81–0.96), respectively. This result suggests that miR-128 is a potential noninvasive biomarker for glioma. In addition, the diagnostic accuracy was assessed by the pooled DOR. The value of DOR ranges from 0 to infinity, with higher values indicating better test discrimination [22]. The DOR of miR-128 was 65.00 (95% CI 26.90–157.10), indicating that the overall accuracy of the miR-128 test for detecting glioma was high. The value of I2 was 0.0%, indicating that there was no significant heterogeneity among studies. The expression level of miR-128 is down-regulated in glioma tissues compared with controls [10,12,13]. Our previous study also showed that the miR-128 expression level was significantly lower in low-grade glioma samples compared with normal controls [23]. In the three studies enrolled in this present meta-analysis, the plasma/serum level of miR-128 was decreased in patients with glioma before surgery compared to control [11–13], and was negatively correlated with low- and high-grade glioma [11,13]. The blood level of miR-128 is elevated postoperation in patients with glioma [11,13], and therefore, miR-128 might be associated with a clinical curative effect. MiR‐128 functions as a vital anti‐oncogene in glioma cells [24]; it can block glioma self-renewal by down-regulation of Bmi-1 expression [25], it can inhibit
2.3. Data extraction and quality assessment Two independent reviewers (Ruofei Liang and Mao Li) screened the articles for the following characteristics: first author, number of patients and controls, publication year, RNA detection methods, cut-off, reference gene, area under the receiver operating characteristic curve, and reported sensitivity and specificity or sufficient data to calculate them. The Quality Assessment of Diagnostic Accuracy Studies (QUADAS) checklist with a maximum score of 14 was used by two reviewers (Ruofei Liang and Mao Li) to estimate the quality of the articles [14]. 2.4. Statistical analysis We assessed the diagnostic value of miR-128 by calculating the pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR) and corresponding 95% CI. The diagnostic odds ratio (DOR) was used to assess the performance of diagnostic tests. All statistical analyses of relevant data were performed using Meta-Disc 1.4 software [15]. The I2 and chi-squared tests were used to evaluate potential heterogeneity between studies. An I2 value of 50% or more was defined as representing significant heterogeneity [16], and a probability value of P less than 0.05 was defined as being statistically significant. 3. Results 3.1. Study selection and quality assessment The initial search returned a total of 417 articles, three of which met our established criteria and were included in the study [11–13]. The three studies entered into this meta-analysis included a total of 191 patients with glioma (24 with Grade I, 33 with Grade II, 53 with Grade III, and with 81 Grade IV), and 73 individuals without tumor. The detailed characteristics of the articles included in this study are Table 1 Summary of studies included in this meta-analysis. First author
Year
Patients (controls)
Detection Method
RNA extraction
Sample types
Cut-off
Reference gene
AUC
SE
SP
DOR
QUADAS score
Q.Wang Q.Wang J. Sun
2012 2014 2015
10(10) 30(10) 151(53)
qRT-PCR qRT-PCR qRT-PCR
Isolation kit Isolation kit Trizol
Plasma Plasma Serum
NR NR 7.139
mmu-miR-295 U6 cel-miR-39
1.00 1.00 0.91
0.90 1.00 0.87
1.00 0.90 0.89
133.00 386.33 51.31
12 12.5 12.5
NR, No reported; SEN, Sensitivity; SPE, Specificity; DOR, Diagnostic odds ratio; AUC, area under the receiver operating characteristic curve; QUADAS score, the quality assessment of diagnostic accuracy studies score.
89
Clinical Neurology and Neurosurgery 160 (2017) 88–91
R.-F. Liang et al.
Fig. 1. Forest plots of sensitivity, specificity and diagnostic odds ratio for miR-128 test in glioma.
References
glioma cell proliferation and enhance apoptosis via inhibition of RhoE in glioma cells [24], and it can also promote cell–cell adhesion by down-regulation of EphB2 expression [26]. Thus, further studies should be undertaken to investigate the role of miR-128 in tumorigenesis and its relationship with the prognosis of glioma. This meta-analysis has several limitations. First, as the potential diagnostic value of miR-128 has only very recently been explored, sample sizes are relatively small; for instance, the study by Wang et al. [11] included only 10 patients with GBM. Hence, there might be a small-study effect. Therefore, further validations of miR-128 in large cohorts and independent studies are needed. Moreover, the miR-128 expression level in circulation varies with the grade of the disease, and there are insufficient data available to analyze each grade of glioma by meta-analysis. Furthermore, many other cancer types show miR-128 dysregulation. However, studies that differentiate glioma from other tumor types are lacking, which might limit the application of miR-128 in clinical settings. Lastly, owing to the limited number of articles in this study, we did not attempt to estimate publication bias or draw a summary receiver operating characteristic curve. In conclusion, the present meta-analysis showed that circulating miR-128 might be a promising noninvasive biomarker for diagnosing glioma. Further studies with larger sample sizes should be performed to confirm these results.
[1] D.C. Adamson, B.A. Rasheed, R.E. Mclendon, et al., Central nervous system, Cancer Biomark. 9 (2010) 193–210. [2] P.Y. Wen, D.A. Reardon, Neuro-oncology in 2015: Progress in glioma diagnosis classification and treatment, Nat. Rev. Neurol. 12 (2016) 69–70. [3] F.G. Davis, V. Kupelian, S. Freels, et al., Prevalence estimates for primary brain tumors in the United States by behavior and major histology groups, Neuro Oncol. 3 (2001) 152–158. [4] R. Stupp, W.P. Mason, M.J. Van Den Bent, et al., Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma, N. Engl. J. Med. 352 (2005) 987–996. [5] Y. Tian, Y. Tian, X. Luo, et al., Identification and characterization of microRNAs related to salt stress in broccoli, using high-throughput sequencing and bioinformatics analysis, BMC Plant Biol. 14 (2014) 226. [6] E.S. Martens-Uzunova, M. Olvedy, G. Jenster, Beyond microRNA–novel RNAs derived from small non-coding RNA and their implication in cancer, Cancer Lett . 340 (2013) 201–211. [7] C.Z. Chen, MicroRNAs as oncogenes and tumor suppressors, N. Engl. J. Med. 353 (2005) 1768–1771. [8] L. Shan, Q. Ji, G. Cheng, et al., Diagnostic value of circulating miR-21 for colorectal cancer: a meta-analysis, Cancer Biomark. 15 (2015) 47–56. [9] A. Fendler, C. Stephan, G.M. Yousef, et al., The translational potential of microRNAs as biofluid markers of urological tumours, Nat. Rev. Urol. 13 (2016) 734–752. [10] J.G. Cui, Y. Zhao, P. Sethi, et al., Micro-RNA-128 (miRNA-128) down-regulation in glioblastoma targets ARP5 (ANGPTL6) Bmi-1 and E2F-3a, key regulators of brain cell proliferation, J. Neurooncol. 98 (2010) 297–304. [11] Q. Wang, P. Li, A. Li, et al., Plasma specific miRNAs as predictive biomarkers for diagnosis and prognosis of glioma, J. Exp. Clin. Cancer Res. 31 (2012) 97. [12] Q. Wang, A. Li, J. Wang, Role of plasma miR-128 in diagnosis and treatment of glioblastoma, Chin. J. MinimInvasive Neurosurg. 19 (2014) 280–282. [13] J. Sun, K. Liao, X. Wu, et al., Serum microRNA-128 as a biomarker for diagnosis of glioma, Int. J. Clin. Exp. Med. 8 (2015) 456–463. [14] W. Penny, W.R. Anne, B.R. Johannes, et al., The development of QUADAS: a tool for the quality assessment of studies of diagnostic accuracy included in systematic reviews, BMC Med. Res. Methodol. 3 (2003) 25. [15] J. Zamora, V. Abraira, A. Muriel, et al., Meta-DiSc: a software for meta-analysis of test accuracy data, BMC Med. Res. Methodol. 6 (2006) 31. [16] J. Dinnes, J. Deeks, J. Kirby, et al., A methodological review of how heterogeneity has been examined in systematic reviews of diagnostic test accuracy, Health Technol. Assess. 9 (2005) 1–113. [17] X. Sun, Z. Yang, Y. Zhang, et al., Prognostic implications of tissue and serum levels of microRNA-128 in human prostate cancer, Int. J. Clin. Exp. Pathol. 8 (2014) 8394–8401. [18] Z. Tian, B. Guo, M. Yu, et al., Upregulation of micro-ribonucleic acid-128
Disclosure of conflicts of interest None.
Acknowledgements This work was supported by the Key Research and Development Project from the Department of Science and Technology of Sichuan Province, China (No. 2017SZ0006). 90
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[19]
[20]
[21] [22]
of test performance, J. Clin. Epidemiol. 56 (2003) 1129–1135. [23] Y. Yuan, W. Xiang, L. Yanhui, et al., Dysregulation of microRNA-128 expression in WHO grades 2 glioma is associated with glioma-associated epilepsy: down-regulation of miR-128 induces glioma-associated seizure, Epilepsy Res. 127 (2016) 6–11. [24] C. Shang, Y. Hong, Y. Guo, et al., miR-128 regulates the apoptosis and proliferation of glioma cells by targeting RhoE, Oncol. Lett. 11 (2016) 904–908. [25] J. Godlewski, M.O. Nowicki, A. Bronisz, et al., Targeting of the Bmi-1 oncogene/ stem cell renewal factor by microRNA-128 inhibits glioma proliferation and selfrenewal, Cancer Res. 68 (2008) 9125–9130. [26] L. Lin, X. Chen, X. Peng, et al., MicroRNA-128 promotes cell–cell adhesion in U87 glioma cells via regulation of EphB2, Oncol. Rep. 30 (2013) 1239–1248.
cooperating with downregulation of PTEN confers metastatic potential and unfavorable prognosis in patients with primary osteosarcoma, Onco Targets Ther. 7 (2014) 1601–1608. M. Skrzypski, P. Czapiewski, K. Goryca, et al., Prognostic value of microRNA expression in operable non-small cell lung cancer patients, Br. J. Cancer 10 (2014) 991–1000. Y. Takahashi, T. Iwaya, G. Sawada, et al., Up-regulation of NEK2 by microRNA-128 methylation is associated with poor prognosis in colorectal cancer, Ann. Surg. Oncol. 21 (2014) 205–212. Y.D. Zhu, L. Wang, C. Sun, et al., Distinctive microRNA signature is associated with the diagnosis and prognosis of acute leukemia, Med. Oncol. 29 (2012) 2323–2331. A.S. Glas, J.G. Lijmer, M.H. Prins, et al., The diagnostic odds ratio: a single indicator
91
Contents lists available at ScienceDirect
Clinical Neurology and Neurosurgery journal homepage: www.elsevier.com/locate/clineuro
Circulating miR-128 as a potential diagnostic biomarker for glioma Ruo-Fei Liang, Mao Li, Yuan Yang, Xiang Wang, Qing Mao, Yan-Hui Liu
⁎
MARK
Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, China
A R T I C L E I N F O
A B S T R A C T
Keywords: Glioma Circulating miR-128 Meta-analysis
Objective: miR-128 in circulation is a promising marker for early diagnosis of glioma. A meta-analysis was performed to evaluate the diagnostic accuracy and clinical value of circulating miR-128 in patients with glioma. Materials and methods: A comprehensive literature search for relevant published articles (last search updated on December 29, 2016) was conducted in the Chinese Biomedical Literature Database, PubMed, and Embase. The quality assessment of diagnostic accuracy studies (QUADAS) tool was used to score the quality of the eligible studies. Meta-Disc 1.4 software was used to test for heterogeneity and to perform the meta-analysis. Results: The three studies included in our study enrolled a total of 191 patients with glioma and 73 individuals without tumor. Using a fixed-effect model analysis, the summary assessments revealed that the pooled sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio were 0.89 (95% CI: 0.84–0.93), 0.90 (95% CI: 0.81–0.96), 8.07 (95% CI: 4.21–15.46), and 0.13 (95% CI: 0.09–0.19), respectively. The diagnostic odds ratio (DOR) of miR-128 was 65.00 (95% CI: 26.90–157.10), indicating that the overall accuracy of the miR128 test for detecting glioma was high. The value of I2 was 0.0%, indicating that there was no significant heterogeneity among studies. Conclusion: The present meta-analysis showed that circulating miR-128 might be a promising noninvasive biomarker for diagnosing glioma.
1. Introduction
involved in tumor development and progression through the dysfunctions of tumor suppressor genes and oncogenes [7]. As miRNAs are key molecules that determine cells’ fates, they could be used as potential biomarkers in tumor diagnosis. Pioneering studies have demonstrated the potential utility of tumor-specific miRNAs as diagnostic biomarkers for tumors in body fluids [8,9]. As a tumor-associated miRNA, miR-128 is strongly down-regulated in human glioma when compared with the corresponding samples of controls [10]. In recent years, additional studies have revealed that miR-128 is significantly down-regulated in the circulation of patients with glioma compared to that in individuals without tumor [11–13]. Therefore, we performed a meta-analysis to estimate the suitability of circulating miR-128 as a biomarker for the early diagnosis of glioma.
Gliomas are defined as tumors arising from glial cells, and they comprise more than 36% of all primary tumor of the central nervous system (CNS) and 80% of all malignant CNS tumors [1,2]. Glioblastoma (GBM) is the most common and malignant form of glioma, accounting for about 50% of all intracranial gliomas [3]. However, even with comprehensive treatment (surgical resection, radiation and chemotherapy), the prognosis is still poor for patients with newly diagnosed GBM; the 2-year survival rate is around 27% and the median survival is 14.6 months [4]. Therefore, investigation of potential minimally invasive biomarkers with high sensitivity and specificity for the early diagnosis of gliomas is urgently needed. The circulating biomarkers of glioma have become a major focus of research. MiRNAs are a class of endogenous small (approximately 20–24 nucleotides) noncoding RNAs that regulate specific target gene expression via a post-transcriptional manner [5]. They have been identified as key regulatory molecules involved in a variety of cellular functions and biological processes, such as metabolism, proliferation, apoptosis, and differentiation [6]. Not surprisingly, dysregulation of the miRNAs pathways affects many cellular functions and biological processes that are routinely altered in tumors. More specifically, they are
⁎
Corresponding author. E-mail address: [email protected] (Y.-H. Liu).
http://dx.doi.org/10.1016/j.clineuro.2017.06.020 Received 24 March 2017; Received in revised form 21 June 2017; Accepted 28 June 2017 Available online 05 July 2017 0303-8467/ © 2017 Elsevier B.V. All rights reserved.
2. Methods 2.1. Literature search A comprehensive literature search for relevant articles published (last search updated on December 29, 2016) in the Chinese Biomedical Literature Database (CBM), PubMed, and Embase was conducted. The key words used for the literature search included: hsa-miR-128; miRNA-
Clinical Neurology and Neurosurgery 160 (2017) 88–91
R.-F. Liang et al.
128; miR-128; microRNA-128; glioma; and brain tumor. No language restrictions were applied. All eligible articles were retrieved. All studies identified by our search strategy were assessed by 2 independent reviewers (Ruofei Liang and Mao Li). Any disagreements on controversial articles were resolved by discussion until a consensus was reached.
summarized in Table 1. Overall, the QUADAS scores of the included articles ranged from 12 to 12.5, which demonstrate that the quality of the articles is acceptable.
2.2. Literature selection
The sensitivity and specificity of miR-128 are shown on a forest plot (Fig. 1). The pooled sensitivity, specificity, PLR, and NLR were 0.89 (95% CI: 0.84–0.93), 0.90 (95% CI: 0.81–0.96), 8.07 (95% CI: 4.21–15.46), and 0.13 (95% CI: 0.09–0.19), respectively, which suggests that miR-128 could be a good blood test marker for glioma diagnosis. The diagnostic accuracy was assessed by the pooled DOR, which was 65.00 (95% CI: 26.90–157.10; Fig. 1), indicating that miR128 has a high diagnostic accuracy for diagnosing glioma. The value of I2 was 0.0%.
3.2. Data analysis
Eligible articles included in this study met the following criteria: (1) the diagnosis of glioma was made based on pathological confirmation; (2) they detected miR-128 in cerebrospinal fluid, plasma, or serum; (3) these studies investigated the relationship between miR-128 expression levels and glioma diagnosis; (4) they selected healthy people or patients with benign disease as the control group; and (5) the articles presented sufficient data to allow for construction of 2 × 2 tables. The exclusion criteria were as follows: (1) the patients were included in other studies; (2) these studies only detected tissue miR-128; (3) the articles were case reports, letters, or reviews; and (4) these articles could not provide enough data to allow construction of 2 × 2 tables.
4. Discussion In recent years, miRNAs have gained wide interests in tumor research for their pivotal role in gene regulation and tumor development. The potential role of miR-128 as a novel diagnostic or prognostic biomarker has been confirmed by accumulated evidence in multiple tumor types, such as prostate cancer, primary osteosarcoma, non-small cell lung cancer, colorectal cancer and acute leukemia [17–21]. An ideal diagnostic biomarker should be reliable, convenient and sensitive. The studies in our study detected circulating miR-128 expression using a qRT-PCR method. Tumor-derived miRNAs in serum or plasma are very accessible, and qRT-PCR is a commonly used analysis technology in clinical practice. Therefore, the purpose of this study was to evaluate the diagnostic role of circulating miR-128 in gliomas through metaanalysis. In the present meta-analysis, we included three studies with a total participant population of 264. We showed that circulating miR-128 can discriminate glioma from controls and had a pooled sensitivity and specificity of 0.89 (95% CI: 0.84–0.93) and 0.90 (95% CI: 0.81–0.96), respectively. This result suggests that miR-128 is a potential noninvasive biomarker for glioma. In addition, the diagnostic accuracy was assessed by the pooled DOR. The value of DOR ranges from 0 to infinity, with higher values indicating better test discrimination [22]. The DOR of miR-128 was 65.00 (95% CI 26.90–157.10), indicating that the overall accuracy of the miR-128 test for detecting glioma was high. The value of I2 was 0.0%, indicating that there was no significant heterogeneity among studies. The expression level of miR-128 is down-regulated in glioma tissues compared with controls [10,12,13]. Our previous study also showed that the miR-128 expression level was significantly lower in low-grade glioma samples compared with normal controls [23]. In the three studies enrolled in this present meta-analysis, the plasma/serum level of miR-128 was decreased in patients with glioma before surgery compared to control [11–13], and was negatively correlated with low- and high-grade glioma [11,13]. The blood level of miR-128 is elevated postoperation in patients with glioma [11,13], and therefore, miR-128 might be associated with a clinical curative effect. MiR‐128 functions as a vital anti‐oncogene in glioma cells [24]; it can block glioma self-renewal by down-regulation of Bmi-1 expression [25], it can inhibit
2.3. Data extraction and quality assessment Two independent reviewers (Ruofei Liang and Mao Li) screened the articles for the following characteristics: first author, number of patients and controls, publication year, RNA detection methods, cut-off, reference gene, area under the receiver operating characteristic curve, and reported sensitivity and specificity or sufficient data to calculate them. The Quality Assessment of Diagnostic Accuracy Studies (QUADAS) checklist with a maximum score of 14 was used by two reviewers (Ruofei Liang and Mao Li) to estimate the quality of the articles [14]. 2.4. Statistical analysis We assessed the diagnostic value of miR-128 by calculating the pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR) and corresponding 95% CI. The diagnostic odds ratio (DOR) was used to assess the performance of diagnostic tests. All statistical analyses of relevant data were performed using Meta-Disc 1.4 software [15]. The I2 and chi-squared tests were used to evaluate potential heterogeneity between studies. An I2 value of 50% or more was defined as representing significant heterogeneity [16], and a probability value of P less than 0.05 was defined as being statistically significant. 3. Results 3.1. Study selection and quality assessment The initial search returned a total of 417 articles, three of which met our established criteria and were included in the study [11–13]. The three studies entered into this meta-analysis included a total of 191 patients with glioma (24 with Grade I, 33 with Grade II, 53 with Grade III, and with 81 Grade IV), and 73 individuals without tumor. The detailed characteristics of the articles included in this study are Table 1 Summary of studies included in this meta-analysis. First author
Year
Patients (controls)
Detection Method
RNA extraction
Sample types
Cut-off
Reference gene
AUC
SE
SP
DOR
QUADAS score
Q.Wang Q.Wang J. Sun
2012 2014 2015
10(10) 30(10) 151(53)
qRT-PCR qRT-PCR qRT-PCR
Isolation kit Isolation kit Trizol
Plasma Plasma Serum
NR NR 7.139
mmu-miR-295 U6 cel-miR-39
1.00 1.00 0.91
0.90 1.00 0.87
1.00 0.90 0.89
133.00 386.33 51.31
12 12.5 12.5
NR, No reported; SEN, Sensitivity; SPE, Specificity; DOR, Diagnostic odds ratio; AUC, area under the receiver operating characteristic curve; QUADAS score, the quality assessment of diagnostic accuracy studies score.
89
Clinical Neurology and Neurosurgery 160 (2017) 88–91
R.-F. Liang et al.
Fig. 1. Forest plots of sensitivity, specificity and diagnostic odds ratio for miR-128 test in glioma.
References
glioma cell proliferation and enhance apoptosis via inhibition of RhoE in glioma cells [24], and it can also promote cell–cell adhesion by down-regulation of EphB2 expression [26]. Thus, further studies should be undertaken to investigate the role of miR-128 in tumorigenesis and its relationship with the prognosis of glioma. This meta-analysis has several limitations. First, as the potential diagnostic value of miR-128 has only very recently been explored, sample sizes are relatively small; for instance, the study by Wang et al. [11] included only 10 patients with GBM. Hence, there might be a small-study effect. Therefore, further validations of miR-128 in large cohorts and independent studies are needed. Moreover, the miR-128 expression level in circulation varies with the grade of the disease, and there are insufficient data available to analyze each grade of glioma by meta-analysis. Furthermore, many other cancer types show miR-128 dysregulation. However, studies that differentiate glioma from other tumor types are lacking, which might limit the application of miR-128 in clinical settings. Lastly, owing to the limited number of articles in this study, we did not attempt to estimate publication bias or draw a summary receiver operating characteristic curve. In conclusion, the present meta-analysis showed that circulating miR-128 might be a promising noninvasive biomarker for diagnosing glioma. Further studies with larger sample sizes should be performed to confirm these results.
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Disclosure of conflicts of interest None.
Acknowledgements This work was supported by the Key Research and Development Project from the Department of Science and Technology of Sichuan Province, China (No. 2017SZ0006). 90
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